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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/cancerres.aacrjournals.org\/sites\/default\/files\/advagg_css\/css__uXgUByez87OKDsgffPHe7u5qNUzr7zOnqWrSJ87THKk__RR-QNYl6SsTObm37M1MaRCUwwzIP19wUZLcqO_pRc1Q__v12QBQujJIS3X9km2EkmMiTVZc6dA23tBQ3YaJyNxyU.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/cdn.jsdelivr.net\/qtip2\/2.2.1\/jquery.qtip.min.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/cancerres.aacrjournals.org\/sites\/default\/files\/advagg_css\/css__HGACIFBlu2o05y3afvqlt5wrE_5Dn6MXsexfuEpeIwg__m4bCC4yOEDGjYhdv5swNtVLewgXQyMt0_Zx9Q9CX1zU__v12QBQujJIS3X9km2EkmMiTVZc6dA23tBQ3YaJyNxyU.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-jnl-aacr-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n \n \n \n \u003Cdiv class=\u0022pane-content\u0022\u003E\n \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 data-highwire-cite-ref-tooltip-instance=\u0022highwire_reflinks_tooltip\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article abstract-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022issue-title\u0022\u003EProceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC\u003C\/div\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003EAbstract\u003C\/h2\u003E\u003Cp id=\u0022p-1\u0022\u003EChronic lymphocytic leukemia (CLL) is characterized by the accumulation of abnormal B-cell development in which mechanisms for cell death have been altered. As the second most common type of leukemia in adults, it progresses at a very slow rate compared to other leukemias and is considered incurable. Approximately 10% of previously untreated patients with CLL exhibit a substantial deletion in the q arm of chromosome 11 (11q22.3), the site of the ATM gene (ataxia telangiectasia mutated). Deletion of this region is associated with rapid disease progression and shorter overall survival. This lesion occurs at increased incidence, 40-50%, in patients who relapse on fludarabine-cyclophosphamide-rituximab chemoimmunotherapy. The residual ATM allele is often mutated, suggesting that the region containing ATM is important for response to chemotherapy. Also, because ATM is critical for repairing double strand breaks that arise after exposure to PARP1 inhibitors and drugs that cause replication fork collapse, identification of tumors that lack ATM function may be a biomarker for specific therapies.\u003C\/p\u003E\u003Cp id=\u0022p-2\u0022\u003EIn order to distinguish CLL disease with ATM non-functional and functional among del(11q22.3) patients characterized by fluorescence in situ hybridization (FISH), we have established an assay of ATM activity in primary CLL cells. It is known that ATM is activated in response to ionizing radiation and will further phosphorylate its downstream targets. We have demonstrated that phosphorylation of KAP1 and Smc1 (both ATM downstream substrates) are primarily dependent on the activity of ATM using cell lines established from a patient with ataxia telangiectasia that are either deficient in ATM function or complemented with the full length gene. In this assay, CLL samples from eight patients with normal FISH karyotype were collected, mock treated or irradiated with a 10 Gy dose, and protein lysates were prepared. The lysates were then combined as a positive pool comparator for the del(11q22-23) CLL samples, and both total and phosphorylated KAP1 and Smc1 proteins were quantitated by immunoblotting. The averaged phosphorylation levels of the KAP1 and Smc1 proteins among the irradiated samples from patients with del(11q22.3) by FISH was calculated and compared with those of the ATM-positive pool. An averaged phosphorylation ratio \u226430% of the positive pool sample was taken as indicative of a deficiency in ATM function. Using this cutoff, we identified five ATM non-functional individuals among ten del(11q22.3) CLL samples isolated from archived stocks. The mutation status of DNA extracted from CLL cells is being analyzed by deep sequencing in reference to the subjects\u2019 T-cell genomic DNA . This assay could be applied to CLL and other tumors at risk for loss of ATM activity, to identify those deficient in ATM function. These individuals may be considered for tumor-specific and personalized therapy targeting ATM deficiency.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003E\u003Cstrong\u003ECitation Format:\u003C\/strong\u003E Yingjun Jiang, Xiaojun Liu, Sijin Wen, Kim-Anh Do, Xiaoping Su, Michael J. Keating, William Wierda, William Plunkett. Quantitation of ATM function in primary CLL cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3528. doi:10.1158\/1538-7445.AM2013-3528\u003C\/p\u003E\u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a92013 American Association for Cancer Research\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003C\/div\u003E \u003C\/div\u003E\n\n \n \u003C\/div\u003E\n\u003C\/div\u003E\n \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/cancerres.aacrjournals.org\/sites\/default\/files\/js\/js_9PNKBZMvg3KusIqJA3bWoKPbbKuSkQg3Pco0vwQasAE.js\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}